Indirect epigenetic testing identifies a diagnostic signature of cardiomyocyte DNA methylation in heart failure

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Christian U. Oeing - , Heidelberg University , Charité – Universitätsmedizin Berlin (Author)
  • Mark E. Pepin - , Heidelberg University  (Author)
  • Kerstin B. Saul - , Heidelberg University  (Author)
  • Ayça Seyhan Agircan - , Heidelberg University  (Author)
  • Yassen Assenov - , German Cancer Research Center (DKFZ) (Author)
  • Tobias S. Merkel - , Heidelberg University  (Author)
  • Farbod Sedaghat-Hamedani - , Heidelberg University  (Author)
  • Tanja Weis - , Heidelberg University  (Author)
  • Benjamin Meder - , Heidelberg University  (Author)
  • Kaomei Guan - , Institute of Pharmacology and Toxicology, Dresden University of Technology (Author)
  • Christoph Plass - , German Cancer Research Center (DKFZ) (Author)
  • Dieter Weichenhan - , German Cancer Research Center (DKFZ) (Author)
  • Dominik Siede - , Heidelberg University  (Author)
  • Johannes Backs - , Heidelberg University  (Author)

Abstract

Precision-based molecular phenotyping of heart failure must overcome limited access to cardiac tissue. Although epigenetic alterations have been found to underlie pathological cardiac gene dysregulation, the clinical utility of myocardial epigenomics remains narrow owing to limited clinical access to tissue. Therefore, the current study determined whether patient plasma confers indirect phenotypic, transcriptional, and/or epigenetic alterations to ex vivo cardiomyocytes to mirror the failing human myocardium. Neonatal rat ventricular myocytes (NRVMs) and single-origin human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and were treated with blood plasma samples from patients with dilated cardiomyopathy (DCM) and donor subjects lacking history of cardiovascular disease. Following plasma treatments, NRVMs and hiPSC-CMs underwent significant hypertrophy relative to non-failing controls, as determined via automated high-content screening. Array-based DNA methylation analysis of plasma-treated hiPSC-CMs and cardiac biopsies uncovered robust, and conserved, alterations in cardiac DNA methylation, from which 100 sites were validated using an independent cohort. Among the CpG sites identified, hypo-methylation of the ATG promoter was identified as a diagnostic marker of HF, wherein cg03800765 methylation (AUC = 0.986, P < 0.0001) was found to out-perform circulating NT-proBNP levels in differentiating heart failure. Taken together, these findings support a novel approach of indirect epigenetic testing in human HF.

Details

Original languageEnglish
Article number9
JournalBasic research in cardiology
Volume118
Issue number1
Publication statusPublished - Dec 2023
Peer-reviewedYes

External IDs

PubMed 36939901

Keywords

Sustainable Development Goals

Keywords

  • DNA methylation, Epigenetics, Heart failure, Pilot study, Precision medicine, Epigenomics, Myocytes, Cardiac/pathology, Humans, Epigenesis, Genetic, Rats, DNA Methylation, Heart Failure/diagnosis, Animals, Induced Pluripotent Stem Cells